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- PDB-6tpd: Fragment-based discovery of pyrazolopyridones as JAK1 inhibitors ... -

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Basic information

Entry
Database: PDB / ID: 6tpd
TitleFragment-based discovery of pyrazolopyridones as JAK1 inhibitors with excellent subtype selectivity
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Inhibitor / Complex
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / thrombopoietin-mediated signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / histone H3Y41 kinase activity / interleukin-5-mediated signaling pathway / interleukin-23-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / Interleukin-23 signaling / positive regulation of leukocyte proliferation / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / positive regulation of MHC class II biosynthetic process / acetylcholine receptor binding / positive regulation of natural killer cell proliferation / positive regulation of platelet activation / growth hormone receptor binding / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / positive regulation of epithelial cell apoptotic process / regulation of receptor signaling pathway via JAK-STAT / positive regulation of cell-substrate adhesion / extrinsic component of cytoplasmic side of plasma membrane / axon regeneration / extrinsic component of plasma membrane / response to hydroperoxide / Interleukin-20 family signaling / growth hormone receptor signaling pathway / Interleukin-6 signaling / negative regulation of cardiac muscle cell apoptotic process / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cell-cell adhesion / peptide hormone receptor binding / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / MAPK1 (ERK2) activation / Prolactin receptor signaling / positive regulation of interleukin-17 production / response to amine / signaling receptor activator activity / mesoderm development / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / response to tumor necrosis factor / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / Erythropoietin activates RAS / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / actin filament polymerization / negative regulation of cytokine production involved in inflammatory response / post-translational protein modification / cellular response to dexamethasone stimulus / SH2 domain binding / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / endosome lumen / positive regulation of receptor signaling pathway via JAK-STAT
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : ...Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-QZ8 / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsHansen, B.B. / Jepsen, T.J. / Larsen, M. / Sindet, R. / Vifian, T. / Burhardt, M.N. / Larsen, J. / Seitzberg, J.G. / Carnerup, M.A. / Jerre, A. ...Hansen, B.B. / Jepsen, T.J. / Larsen, M. / Sindet, R. / Vifian, T. / Burhardt, M.N. / Larsen, J. / Seitzberg, J.G. / Carnerup, M.A. / Jerre, A. / Moelck, C. / Rai, S. / Nasipireddy, V.R. / Ritzen, A.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity.
Authors: Hansen, B.B. / Jepsen, T.H. / Larsen, M. / Sindet, R. / Vifian, T. / Burhardt, M.N. / Larsen, J. / Seitzberg, J.G. / Carnerup, M.A. / Jerre, A. / Molck, C. / Lovato, P. / Rai, S. / Nasipireddy, V.R. / Ritzen, A.
History
DepositionDec 13, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1812
Polymers33,9561
Non-polymers2251
Water2,162120
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14530 Å2
Unit cell
Length a, b, c (Å)107.411, 69.669, 50.798
Angle α, β, γ (deg.)90.00, 98.45, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 33955.879 Da / Num. of mol.: 1 / Mutation: Y1007F/Y1008F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-QZ8 / 3-methyl-4-phenyl-2,7-dihydropyrazolo[3,4-b]pyridin-6-one


Mass: 225.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 120 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.77 Å3/Da / Density % sol: 55.57 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 2.1M Na Malonate pH 6.0/6.5, 0.1M glycine pH 8.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.99→53.18 Å / Num. obs: 25481 / % possible obs: 99.9 % / Redundancy: 3.3 % / Rrim(I) all: 0.181 / Net I/σ(I): 7.7
Reflection shellResolution: 1.99→2.09 Å / Mean I/σ(I) obs: 3.3 / Num. unique obs: 3357 / Rrim(I) all: 0.887

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
Aimlessdata scaling
PHASER5.8.0253phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L3A

5l3a


Resolution: 1.99→53.18 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.884 / SU B: 11.463 / SU ML: 0.159 / Cross valid method: THROUGHOUT / ESU R: 0.192 / ESU R Free: 0.182 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.27759 1203 4.7 %RANDOM
Rwork0.22341 ---
obs0.22599 24165 99.4 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.233 Å2
Baniso -1Baniso -2Baniso -3
1-0.3 Å20 Å2-0.59 Å2
2---0.09 Å2-0 Å2
3----0.04 Å2
Refinement stepCycle: LAST / Resolution: 1.99→53.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2386 0 17 120 2523
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192456
X-RAY DIFFRACTIONr_bond_other_d0.0010.022278
X-RAY DIFFRACTIONr_angle_refined_deg1.3771.9043308
X-RAY DIFFRACTIONr_angle_other_deg1.0932.945297
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2095288
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.82324.048126
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.15215462
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2291519
X-RAY DIFFRACTIONr_chiral_restr0.0810.2347
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022699
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02511
X-RAY DIFFRACTIONr_mcbond_it7.3430.7941154
X-RAY DIFFRACTIONr_mcbond_other7.3410.7941153
X-RAY DIFFRACTIONr_mcangle_it9.351.1611442
X-RAY DIFFRACTIONr_mcangle_other9.351.1611442
X-RAY DIFFRACTIONr_scbond_it9.4261.2451301
X-RAY DIFFRACTIONr_scbond_other9.4231.2451302
X-RAY DIFFRACTIONr_scangle_other11.7881.6371866
X-RAY DIFFRACTIONr_long_range_B_refined13.4669.9352823
X-RAY DIFFRACTIONr_long_range_B_other13.4939.7972805
LS refinement shellResolution: 1.99→2.042 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 81 -
Rwork0.32 1745 -
obs--98.86 %
Refinement TLS params.Method: refined / Origin x: 123.599 Å / Origin y: -12.656 Å / Origin z: 12.681 Å
111213212223313233
T0.2354 Å20.0148 Å20.0583 Å2-0.0897 Å20.0057 Å2--0.0145 Å2
L0.4317 °20.2948 °20.2488 °2-1.3992 °20.3445 °2--1.1122 °2
S-0.0062 Å °0.1072 Å °-0.0015 Å °-0.1489 Å °0.0166 Å °-0.0451 Å °-0.0286 Å °0.0346 Å °-0.0104 Å °

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